Brain complexity: self-organizing molecules speed reactions (Introduction)

by David Turell , Thursday, August 16, 2018, 00:04 (2292 days ago) @ David Turell

Especially found for immune reaction stimulation at synapses:

https://medicalxpress.com/news/2018-08-protein-droplets-neurons-ready-immune.html

"Inside cells, where DNA is packed tightly in the nucleus and rigid proteins keep intricate transport systems on track, some molecules have a simpler way of establishing order. They can self-organize, find one another in crowded spaces, and quickly coalesce into droplets—like oil in water.

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"In one study, HHMI Investigator Pietro De Camilli and colleagues have shown how liquid droplets inside neurons keep signals racing through the brain. In the other, a team led by HHMI Investigator Zhijian "James" Chen has discovered that droplets of a danger-sensing enzyme generate signals that launch an immune response.

"The formation of these droplets is a phenomenon known as phase separation. In the last decade, biologists have watched proteins and RNA molecules rapidly organize themselves into droplets inside test tubes and spotted liquid-like droplets inside cells.

"But it hasn't always been clear what, if any, advantages these droplets provide. The new discoveries from De Camilli and Chen offer an answer—a clear link between phase separation and biological function.

"In his lab at the Yale School of Medicine, De Camilli studies how neurons manage the neurotransmitters that relay signals between neighboring cells. Inside cells, these signaling molecules reside in tiny membrane-bound spheres called synaptic vesicles. When an incoming message arrives, vesicles release their contents into the synapse, the space across which a cell communicates with its neighbor.

"Each cell can store thousands of vesicles in structures called nerve terminals. At times, a single terminal may need to release more than 100 synaptic vesicles in a second. So it's crucial that the reserves are readily accessible, De Camilli says.

"No membrane or structure encases the clusters, and De Camilli says he wondered for decades what held them together. When he heard about other biologists' phase separation discoveries, he suspected the phenomenon might also apply to synapsin.

"Postdoctoral researcher Dragomir Milovanovic was struck by some features of synapsin that resemble those of other proteins that can phase separate. He dropped a solution of fluorescent synapsin molecules onto a cover slip and watched them quickly coalesce into droplets. Occasionally, two droplets merged into one, just like oil droplets finding one another in water. In other experiments, Milovanovic observed individual synapsin molecules moving freely between droplets. Just as the scientists had guessed, synapsin was behaving like a fluid.

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"In nerve cells, droplets of synaptic vesicles offer a clear advantage, he says: a ready supply of neurotransmitter messengers. The finding explains how neurons can keep up when the demand for neurotransmitter release is high.

"At the University of Texas Southwestern Medical Center, Chen's work with liquid droplets helped explain a different puzzle: how a DNA-sensing enzyme alerts the immune system to infection. That enzyme is cyclic GMP-AMP synthase, or cGAS, which Chen's lab discovered in 2012

The enzyme floats in the cytoplasm of cells and switches on when it encounters DNA. Since a cell's own genes are contained in its nucleus and mitochondria, DNA in the cytoplasm is a signal that something is amiss—usually, that a pathogen is present. cGAS responds by generating cGAMP, a messenger molecule that calls on the body's first line of defense—the innate immune system—to counter the suspected threat.

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"Du's experiments established that the enzyme forms droplets only in the presence of DNA. These droplets are critical for pathogen sensing—they appear to act as microreactors, bringing the enzyme together with everything it needs to generate the immune-activating messenger molecule, Chen says. Longer pieces of DNA are better at promoting droplet formation than short ones.

"And because DNA must be present above a threshold level before these droplets form, cGAS rarely calls the innate immune system to action unnecessarily. Waiting until enough DNA is present to trigger phase separation effectively lets the enzyme distinguish friends from foe, Chen says.

"Sometimes, he notes, cells fail to achieve that fine balance. Then, cGAS, and consequently the immune system, overreact to a cell's own DNA, resulting in autoimmune diseases such as lupus or arthritis. Understanding how phase separation regulates this enzyme may help scientists devise ways to correct such problems. "

Comment: A cleverly designed rapid response system. This had to have appeared very early on to protect against infections. Too complex for chance evolution.